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Quorum sensing (QS), a key regulator of virulence and biofilm formation, offers a promising avenue to mitigate resistance by disarming pathogens without bactericidal pressure. This study investigates the repurposing of nitroimidazoles as anti\u2010QS and anti\u2010virulence agents at subminimum inhibitory concentrations (sub\u2010MICs). In Silico analyses, including molecular docking and molecular dynamics (MD) simulations, were performed to investigate ligand\u2010receptor interactions with structurally distinct Lux\u2010type QS receptors and assess binding stability and conformational dynamics over time. In Vitro assays evaluated the effects of representative nitroimidazoles, metronidazole (MET) and secnidazole (SEC), on QS\u2010controlled phenotypes, including violacein production in\n                    <jats:italic>Chromobacterium violaceum<\/jats:italic>\n                    and biofilm formation and protease activity in\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    ,\n                    <jats:italic>Acinetobacter baumannii<\/jats:italic>\n                    ,\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    , and\n                    <jats:italic>Proteus mirabilis<\/jats:italic>\n                    . In Vivo efficacy was assessed using a murine infection model and HeLa cell invasion assays. Molecular docking revealed high\u2010affinity binding to QS receptors, corroborating their mechanistic interference. Sub\u2010MIC MET\/SEC significantly suppressed violacein synthesis, biofilm biomass, and protease secretion in Gram\u2010negative pathogens. Both compounds reduced bacterial invasiveness in HeLa cells and In Vivo protected mice from lethal\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    infections. Crucially, nitroimidazoles attenuated virulence without affecting bacterial viability, preserving microbial ecology. These findings position nitroimidazoles as dual\u2010function agents; antimicrobial at bactericidal doses and anti\u2010virulence at sub\u2010MICs. Their validated efficacy across In Silico, In Vitro, and In Vivo models underscores their potential as adjunctive therapies, bridging the gap between drug repurposing and next\u2010generation anti\u2010infective development.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70101","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T03:01:37Z","timestamp":1747623697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Repurposing Nitroimidazoles: A New Frontier in Combatting Bacterial Virulence and Quorum Sensing via In Silico, In Vitro, and In Vivo Insights"],"prefix":"10.1002","volume":"86","author":[{"given":"El\u2010Sayed","family":"Khafagy","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy Prince Sattam Bin Abdulaziz University Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Al","family":"Saqr","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy Prince Sattam Bin Abdulaziz University Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-8536","authenticated-orcid":false,"given":"Bjad K.","family":"Almutairy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy Prince Sattam Bin Abdulaziz University Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed F.","family":"Aldawsari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy Prince Sattam Bin Abdulaziz University Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr Selim Abu","family":"Lila","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy University of Ha'il Ha'il Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3049-4617","authenticated-orcid":false,"given":"Tarek S.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy King Abdulaziz University Jeddah Saudi Arabia"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy Zagazig University Zagazig Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-4803","authenticated-orcid":false,"given":"Wael A. 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